Synthesis of 2-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl) quinazolin-4(3H)-one derivatives

Cite this paper: Vietnam J. Chem., 2021, 59(1), 73-78 Article DOI: 10.1002/vjch.202000122 73 Wiley Online Library © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH Synthesis of 2-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl) quinazolin-4(3H)-one derivatives Srinivasa Reddy Bireddy1, Mohammad Rafeeq2, Venkata Ramana Reddy Chittireddy2* 1Department of Chemistry, Mahatma Gandhi Institute of Technology, Gandipet, Hyderabad, India 500075 2Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, India 500085 Submitted July 17, 2020; Accepted November 8, 2020 Abstract A simple, synthesis of 2-(3-methyl-5-oxo-4, 5-dihydro-1h-pyrazol-1-yl) quinazolin-4(3H)-one 6(a-d) derivatives, an easy, clean, and economical methodology has been defined. The development of a new pathway for the preparation of substituted derivatives of Quinazoline Pyrazole is highlighted in this report. The mild, inexpensive polyphosphoric acid has proven to be an effective catalyst for excellent yields in the above multi-component reaction. Widely available and mostly benign catalyst and easy purification are among the several attractive features. Keywords. Anthranilamide, ethyl acetoacetate, 2-hydrazinoquinazolinone, polyphosphoric acid, hydrazine hydrate, pyrazol. 1. INTRODUCTION Quinazolinones based drugs are known to possess various biological activities such as anti- inflammatory,[1-2] anti-malarial,[3-5] anticonvulsant,[6] anti-hypertensive,[7] anti-tumor,[8- 11]. 2-Thioquinazolinones possess good pharmacological properties,[12-18] antimicrobial,[19] antibacterial,[20-24] anti-cancer,[25-28] and antiviral.[29] Because of this broad range of pharmacological activities, the quinazolinone derivatives have been the target of organic synthetic efforts.[30-32] Polyphosphoric acid (PPA) has been employed as an efficient protic acid catalyst for numerous organic reactions.[33] However no significant major work is reported on reactions of 2-hydrazinoquinazolinone with β- ketoesters and the subsequent chemical modifications of the condensation products, we report here with the studies on the condensation of hydrazinoquinazolin-4(3H)-ones with ethyl acetoacetate under different conditions. 2. MATERIALS AND METHODS General Conditions. Melting points are uncorrected and were determined in DBK programmable Melting point apparatus. TLC was run on silica gel- G and visualization was done using iodine or UV light. IR spectra were recorded using a Perkin-Elmer 1000 instrument in KBr pellets. 1H-NMR spectra were recorded in DMSO - d6 using TMS an internal standard operating at 400 MHz. Preparation of 5 from 3 and 4 A mixture of 2-hydrazinoquinazolin-4(3H)-ones 3 (a-b) (10 mM) β-ketoesters 4(a-b) (10 mM) and acetic acid (15 ml) was stirred at room temperature for 10-20 min. and then poured into ice-cold water (25 ml). The separated solid was filtered, washed with water (2x10 ml) and dried. The products were recrystallized from methanol to obtain pure 5(a-d). 5a (i.e. R1 = H, R2 = CH3): Yield: 2.1 g (71 %); m.p. 114-115 °C (MeOH) (for spectral data, please see under Results and Discussion). 5b (i.e. R1=H, R2=Ph): Yield: 2.0 g (70 %); m.p. 221-223 °C (MeOH); IR (KBr): 3234 cm-1 (very broad, two NH), 1710, 1680 cm-1 (strong, sharp, due to C=O); 1H-NMR (400 MHz, DMSO-d6/TMS):  1.9 (t, 3H, CH3), 2.8 (s, 2H, CH2), 3.49 (t, 2H, CH2), 7.1-8.21 (m, 9H, aromatic protons), 10.3 (s, broad, 2H, NH, D2O, exchangeable); 13C NMR (100 Hz, DMSO-d6/TMS): δ 11.7, 14.1, 37.4, 61.0, 120.8, 126.6, 126.7, 127.3, 128.3, 128.4, 128.5, 128.6, 128.8, 128.9, 133.4, 146.9, 153.3, 153.5, 161.0, 165; LCMS: m/z 350 [M+.+1]. 5c (i.e. R1=Ph, R2=CH3): Yield: 1.80 g (68 %); m.p. 140-141 oC (MeOH) (Lit14 142 oC); IR (KBr): Vietnam Journal of Chemistry Venkata Ramana Reddy Chittireddy et al. © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 74 3253 cm-1 (very broad, medium due to NH), 1715, 1680 cm-1 (strong, sharp, due to C=O); 1H-NMR (400 MHz, DMSO-d6/TMS):  1.9 (t, 3H, CH3), 2.1 (s, 3H, CH3), 2.8 (s, 2H, CH2), 3.49 (t, 2H, CH2), 6.80-8.06 (m, 9H, aromatic protons); 13C-NMR (DMSO-d6/TMS) 11.7, 14.1, 37.4, 61.0, 120.8, 126.6, 126.7, 127.3, 128.3, 128.4, 128.5, 128.6, 128.8, 128.9, 133.4, 146.9, 153.3, 153.5, 161.0, 165; LCMS: m/z 364 [M+.+1]. 5d (i.e. R1=Ph, R2=Ph): Yield: 1.80 g (68 %); m.p. > 250 oC (MeOH); IR (KBr): 3241 cm-1 (very broad, medium, due to NH), 1703, 1671 cm-1 (strong, sharp, due to C=O); 1H-NMR (400 MHz, DMSO-d6/TMS):  1.9 (t, 3H, CH3), 2.8 (s, 2H, CH2), 3.49 (t, 2H, CH2), 7.16-8.06 (m, 14H, aromatic protons), 10.9 (s, broad, 1H, NH); LCMS; 13C NMR (DMSO-d6/TMS) δ 14.1, 28.8, 61.0, 120.8, 126.6, 126.7, 126.8, 127.3, 127.8, 128.3, 128.4, 128.5, 128.6, 128.8, 128.8, 128.9, 133.4, 146.9, 153.3, 153.5, 161.0, 165; m/z 426 [M+.+1]. Preparation of 6 from 5 (General Procedure) A solution of 5 (a-d) (10 mM) in acetic acid was refluxed for 2-3 hr. The reaction mixture was monitored by TLC. After completion of the reaction, the mixture was poured into ice-cold water (25 ml). The separated solid was filtered, washed with water (2x10 ml) and dried. This product was recrystallized from a suitable solvent to obtain pure 6(a-d). 6a (i.e. R1=H, R2=CH3): Yield: 2.1 g (69 %); m.p. 236-237 oC (AcOH) (For Spectral data please see under Results and Discussion). 6b (i.e. R1=H, R2=Ph): Yield: 2.05 g (68 %); m.p. >250 oC (AcOH); IR (KBr): 3240 cm-1 (very broad, due to NH), 1690, 1640 cm-1 (strong, sharp, due to C=O); 1H-NMR (400 MHz, DMSO-d6/TMS):  2.12 (s, 2H, CH2), 7.05-8.31 (m, 9H, aromatic protons), 12.10 (s, broad, 1H, NH, D2O, exchangeable); 13C NMR (100 MHz, DMSO-d6/TMS): δ 35.5, 61.0, 120.8, 126.6, 126.7, 127.3, 128.3, 128.4, 128.5, 128.6, 128.8, 128.9, 133.4, 146.9, 153.3, 153.5, 161.0, 165; LCMS : m/z 304 [M+.+1]. 6c (i.e.R1=Ph, R2=CH3): Yield: 1.7 g (65 %); (AcOH); m.p. 358 oC (Lit,[36] MP 360 oC); IR (KBr): 1685, 1615 cm-1 (strong, sharp, due to C=O); 1H- NMR (400 MHz, DMSO-d6/TMS):  1.81 (s, 3H, CH3), 2.75 (s, 2H, CH2), 7.16-8.36 (m, 9H, aromatic protons); 13C NMR (DMSO-d6/TMS): δ 42.7, 120.8, 126.6, 126.7, 127.3, 128.3, 128.4, 128.5, 128.6, 128.8, 128.9, 133.4, 146.9, 153.3, 153.5, 161.0, 165; LCMS; m/z 318 [M+.+1]. 6d (i.e. R1=Ph, R2=Ph): Yield: 1.7 g (65 %); m.p. >250 oC (EtOH); IR (KBr): 1687 cm-1 (strong, sharp, due to C=O); 1H-NMR (DMSO-d6/TMS):  2.32 (s, 2H, CH2), 7.16-8.36 (m, 14H, aromatic protons); 13C NMR (DMSO-d6/TMS): δ 35.5, 61.0, 120.8, 126.6, 126.7, 126.8, 127.3, 127.8, 128.3, 128.4, 128.5, 128.6, 128.8, 128.8, 128.9, 133.4, 146.9, 153.3, 153.5, 161.0, 165; LCMS : m/z = 380.13 [M+.+1]. Alternative preparation of 6 from 3 and 4 in polyphosphoric acid (PPA) (Method-A): A mixture of 2-hydrazinoquinazolinones 3(a-b), β- ketoesters 4(a-b) and polyphosphoric acid (10 mL) was heated at 110 oC for 20-30 min. with occasional stirring of the mixture by swirling the flask. At the end of this period, the mixture was poured into ice- cold water (50 mL), neutralized with sodium bicarbonate solution (10 %, 5 mL). The separated solid was filtered, washed with water (2x10 mL) and dried. The product was recrystallized from acetic acid to obtain pure 6(a-d). 6a- 2.96 gm (95 %) 6b- 2.96 gm (95 %) 6c- 2.91 gm (94 %) 6d- 2.91 gm (94 %) Alternative preparation of 6 from 3 and 4 in acetic acid (Method-B) A solution of 2-hydrazinoquinazolinones 3(a-b), β- ketoesters 4(a-b) and acetic acid (20 mL) was refluxed for 3-4 hrs. After completion of the reaction, the mixture was poured into ice-cold water (50 mL). The separated solid was filtered, washed with water (2 x10 mL) and dried. The product was recrystallized from acetic acid to obtain pure 6(a-d). 3. RESULTS AND DISCUSSION Commercially available anthranilamide (1) was treated with carbon disulfide in ethanol containing KOH resulted in 2-mercaptoquinazolin-4(3H)-one (2). The latter was heated with hydrazine hydrate in ethanol to obtain 2-hydrazinoquinazolin-4(3H)-one 3a (R1=H). 2-Hydrazinoquinazolin-3-phenyl-4(3H)- one (3b, i.e. 3, R1=Ph), the other starting material, was prepared by refluxing the commercially available anthranilic acid with phenylisothiocyanate in acetic acid giving 2-mercapto-3-phenylquinazolin- 3H-4-one (2b, i.e. 2, R1=Ph) followed by treatment of the latter with hydrazine hydrate in refluxing ethanol for 3 hrs. Treatment of 2-hydrazinoquinazolin-4(3H)-one (3a) with ethyl acetoacetate (4a) in acetic acid at RT for about 15 min. resulted in the formation of ethyl 3-(2-(4-oxo-3, 4-dihydroquinazolin-2- yl)hydrazono)butanoate (5a). It has been characterized in the present work by spectral methods. Thus, its IR (KBr) showed a broad and Vietnam Journal of Chemistry Synthesis of 2-(3-methyl-5-oxo-4,5-dihydro © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 75 medium absorption band at ~3200 cm-1 assignable to the NH group. The strong and sharp absorptions at 1730 (ester) cm-1 and at 1671 cm-1 (amide) in the IR spectrum were assigned to two carbonyl groups. Its 1H-NMR (400 MHz, DMSO-d6) showed signals at δ 1.9 (t, 3H, CH3),  2.49 (s, 3H, CH3), 2.8 (s, 2H, CH2), 6.8-8.1 (m, 4H, all aromatic protons), 10.2 (broad, 2H, -NH, D2O, exchangeable). Its 13C NMR spectrum showed signals at δ 11.7, 14.1, 37.4, 61.0, 120.8, 126.6, 126.7, 127.3, 133.4, 146.9, 153.3, 153.5, 161.0, and 165. Its mass spectrum showed the molecular ion peak at m/z = 323 corresponding to a molecular mass of 322 when recorded in the Q+1 mode. Scheme 1: Synthesis of 6a-d The above reaction of ethyl acetoacetate with 3a was extended to the other β-ketoester, i.e. ethyl 3- oxo-3-phenylpropanoate (4b) and also the reaction of 3b with 4a & 4b was carried out. The products obtained were assigned structures 5(b-d) (table 1) based on their spectral data. For details, please see the Experimental Section (scheme 1). Table 1: Synthesis of 5(a-d) from 3(a-b) and 4(a-b) Starting β-keto ester Product Reaction, Time (min) Yield (%) 3a (R1=H) 4a (R2=CH3) 5a (i.e. R1=H, R2=CH3) 15 71 3a (R1=H) 4b (R2=Ph) 5b (i.e. R1=H, R2=Ph) 15 70 3b (R1=Ph) 4a (R2=CH3) 5c (i.e. R1=Ph, R2=CH3) 18 68 3b (R1=Ph) 4b (R2=Ph) 5d (i.e. R1=Ph, R2=Ph) 18 68 When the above product 5a (i.e. 5, R1=H) was refluxed in acetic acid for about 2 hr, there resulted in the formation of the intramolecularly cyclized product, i.e. 2-(3-methyl-5-oxo-2, 5-dihydro-1H- pyrazol-1-yl) quinazolin-4(3H)-one 6a. Its structure was assigned based on its spectral data. Thus, its IR (KBr) spectrum showed a broad, medium absorption at ≈ 3212 cm-1 due to NH or OH groups and strong, sharp absorptions at 1688, 1609 cm-1 due to the two carbonyl groups. Its 1H-NMR (400 MHz, DMSO-d6) showed signals at  2.15 (s, 3H, CH3), 5.21 (s, 1H, =CH-), 7.33-8.02 (m, 4H, aromatic protons), 12.75 (s, broad, 2H, NH, D2O exchangeable). Its 13C-NMR spectrum showed signals at δ 33.81, 122.44, 123.86, 127.63, 129.38, 135.27, 135.39, 136.88, 144.02, 162.06 and 165.14. Its mass spectrum showed the molecular ion peak at m/z 243 corresponding to a molecular mass of 242 when recorded in the Q+1 mode. The above reaction is found to be a general one and has been extended to 3(b-d) and the products thus obtained were assigned structures 4(b-d) (table 2) based on spectral data (see in Experimental section). Vietnam Journal of Chemistry Venkata Ramana Reddy Chittireddy et al. © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 76 2-Hydrazinoquinazolinone (3) attacks the carbonyl carbon of the ethyl acetoacetate 4 to afford the hydrazone derivative 5. Then, the quinazolinone ring attached nitrogen of 5 attacks the carbonyl carbon of the ester group followed by loss of elements of ethanol and subsequent tautomerization lead to pyrazoloquinazolinone 4. Treatment of 2-hydrazinoquinazolin-4(3H)-one (3a) with ethyl acetoacetate (4a) in polyphosphoric acid at 110 oC for about 30 min. resulted in the formation of the intramolecularly cyclised product, i.e. 2-(3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1- yl)quinazolin-4(3H)-one 6a. Its structure was assigned based on its spectral data. The above reaction has been found to be a general one and has been extended to 3(b-d) and the products thus obtained were assigned structures 4(b-d) (table 3) on the based on spectral data. Table 2: Synthesis of 6a-6d from 5a-5d Starting Material Product Time (hr) Yield (%) 5a (i.e. R1=H, R2=CH3) 6a (i.e. R1=H, R2=CH3) 2 69 5b (i.e. R1=H, R2=Ph) 6b (i.e. R1=H, R2=Ph) 3 68 5c (i.e. R1=Ph, R2=CH3) 6c (i.e. R1=Ph, R2=CH3) 3 65 5d (i.e. R1=Ph, R2=Ph) 6d (i.e. R1=Ph, R2=Ph) 3 65 Plausible Mechanism Table 3: Synthesis of 6(a-d) from 3(a-b) and 4(a-b) Starting β-keto ester Product Reaction time (min) Yield (%) 3a (R1=H) 4a (R2=CH3) 6a (i.e. R1=H, R2=CH3) 30 95 3a (R1=H) 4b (R2=Ph) 6b (i.e. R1=H, R2=Ph) 30 95 3b (R1=Ph) 4a (R2=CH3) 6c (i.e. R1=Ph, R2=CH3) 30 94 3b (R1=Ph) 4b (R2=Ph) 6d (i.e. R1=Ph, R2=Ph) 30 94 Preparation of 6a form 3a&4a in different methodology S.No Solvent Catalyst Reaction time (hr) Temperature (oC) Yield (%) 1 PPA ---- 2 110 95 2 Methanol ACOH 15 65 62 3 Ethanol ACOH 15 78 52 4 IPA ACOH 10 82 60 5 Methanol --- 20 65 51 6 --- ACOH 2 110 69 Vietnam Journal of Chemistry Synthesis of 2-(3-methyl-5-oxo-4,5-dihydro © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 77 4. CONCLUSION A straight forward, clean synthesis of 2-(3-methyl- 5-oxo-4,5-dihydro-1H-pyrazol-1-yl) quinazolin- 4(3H) one 6(a-d), a simple, clean, and affordable strategy has been characterized. Phosphoric acid in the above multi-component reaction has proved to be an efficient catalyst for excellent yields. Among the many attractive features are the readily available and often benign catalyst and fast purification. Two distinct routes have been synthesized in order to establish an effective route for compound 6(a-d). The condensation of 3 to 4 in one pot of polyphosphoric acid synthesis is found to be an effective route for product synthesis (6a-d). The reaction time is very fast and the yield is 95 %. Acknowledgement. The authors are grateful to Jawaharlal Nehru Technological University Hyderabad, India for providing necessary facilities to carry out this work. REFERENCES 1. S. E. Abbas, F. M. Awadallah, N. A. Ibrahin, E. G. Said, G. M. Kamel. 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